Semi-synthetic flavonoid derivatives from Boesenbergiarotunda induce extrinsic apoptosis pathway via Caspase-3 and Caspase-8 in HCT116 Colon Cancer cell lines.

Colorectal cancer ranks as the second most common cancer and the leading cause of cancer-related deaths globally. Phytochemicals like flavonoids from Boesenbergia rotunda showed potential anti-cancer activities. Chemical structures of the parental compounds of flavonoids were modified by conjugating with an acryloyl group to form semi-synthetic flavonoid derivatives to increasing in anti-colon cancer activities. 7-Acryloyloxypinocembrin (5) showed potential antiproliferative activities of IC50 value of 1.87 ± 0.17 μM in HCT116. In addition, compound 5 showed low cytotoxicity in Vero cells with an IC50 value of 2.84 ± 0.13 μM which is two-fold less cytotoxic than osimertinib. Biological mechanisms studies indicated that compound 5, HCT116 cells demonstrated a two-fold increase in apoptotic cell death. Subsequently, compound 5 upregulated caspase-8 and LC3, triggering the upregulation of caspase-3 and leading to the activation of both the extrinsic apoptosis pathway and the autophagy pathway. Network pharmacology analysis highlighted TNF-α receptor is a key gene associated with the extrinsic apoptosis pathway in HCT116 cells treated with compound 5. Molecular dynamics simulation confirmed the strong interaction between compound 5 and TACE, a crucial element in the EGFR and IL-6 signaling pathway's reduction which may lead to a decline in the survival rate of colon cancer. These findings indicate compound 5 as a promising anti-colon cancer drug candidate.